Drugs for the treatment of cancer and other diseases have a so-called “therapeutic window”. In the case of cancer, the therapeutic window defines the drug dosage that can kill cancer cells preferentially to normal cells, thereby establishing a safety range for the use of the drug. The therapeutic window for conventional chemotherapeutics is narrow with, in many cases, significant adverse effects coinciding with marginal slowing of tumour growth. Targeted treatments that spare normal cells are urgently needed.
Therapeutic antibodies form a newer class of cancer therapies that specifically target an antigen presented on the surface of cancer cells. When the target surface protein is unique to the cancer cell, adverse antibody effects on normal cells can be avoided. However, for the majority of antigens, target expression is not restricted completely to tumour cells, with some normal cells also expressing the antigen. In these cases, the antibody may have an effect on normal cells as well as tumor cells, leading to “on-target, off-tissue” adverse events. In the case of the ErbB2 antigen, because it is present on the surface of normal cells in cardiac tissue as well as on breast cancer cells, the clinical use of erbB2-targeting therapeutics is associated with adverse events that include cardiac toxicity. The incidence and degree of adverse events is considerably increased when given in combination with chemotherapeutics, particularly anthracyclines.
Considering the efficacy of anti-erbB2 therapies in treating patients that overexpress erbB2, the risk associated with cardiac toxicity is currently considered acceptable when managed properly. The risk of anti-erbB2 therapy-associated cardiac toxicity can be reduced by avoiding co-administration with anthracyclines, or by administering anti-erbB2 therapy and chemotherapeutics consecutively.
Currently, routine LVEF monitoring is performed to assess cardiac function in patients that are prescribed anti-erbB2 therapies, especially when given in combination with anthracyclines. This is a time-consuming and expensive process which requires patient compliance.
Efforts to improve upon erbB2 antibodies are aimed at generating antibodies having even greater affinity for the target antigen. For instance, U.S. Pat. No. 7,435,797 issued Oct. 14, 2008 describes a variety of trastuzumab analogs in which amino acid substitution is used to further increase target affinity. Substitutions are made at sites within different complementarity determining regions oftrastuzumab.
It would be desirable to provide an erbB2 antibody that is useful to treat subjects presenting with erbB2 over-expressing disease cells, while avoiding significant interaction with cardiac and other normal cells that also present the erbB2 antigen.
It is an object of the present invention to provide therapeutic antibodies, and fragments and conjugates thereof that bind effectively to a given target only when that target is presented at a relatively higher density characteristic of a disease state.
It is a further object of the present invention to provide such antibodies, fragments and conjugates in pharmaceutical compositions, particularly for therapeutic and diagnostic use.
It is a further object of the present invention to provide a method useful, in a subject in need thereof, to control the growth of disease cells that present erbB2 at a density greater than normal erbB2 density, while avoiding or minimizing adverse effects on normal cells.